Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan.
Am J Physiol Endocrinol Metab. 2013 Nov 1;305(9):E1115-23. doi: 10.1152/ajpendo.00401.2013. Epub 2013 Aug 27.
The liver is an essential metabolic organ. In addition to metabolizing glucose and lipids, hepatocytes also secrete various cytokines that modulate both hepatocyte metabolism and liver inflammation. Hepatocyte injury and death and liver inflammation are the major contributors to liver diseases, including nonalcoholic steatohepatitis (NASH). Anatomic locations have a profound effect on hepatocyte metabolism, and liver zonation describes the metabolic heterogeneity of hepatocytes along the portovenous axis. However, it is unclear whether hepatocyte heterogeneity is affected by intrinsic factors and whether dietary fat, a risk factor for NASH, has distinct detrimental effects on different hepatocyte subpopulations. Here, we showed that mouse livers contained both high-lipid and low-lipid subpopulations of hepatocytes. The high-lipid subpopulation was more susceptible to injury and apoptosis and produced more proinflamatrory cytokines after treatment with endotoxin and saturated fatty acids. Dietary fat consumption further increased fatty acid uptake, intracellular lipid levels, hepatocyte injury and death, and the expression of proinflammatory cytokines in the high-lipid subpopulation. In contrast, dietary fat slightly increased lipid levels, cell death, and expression of proinflammatory cytokines in the low-lipid subpopulation. The low-lipid subpopulation produced more glucose. Fat consumption further activated the gluconeogenic program in the low-lipid, but not the high-lipid, subpopulations. These data suggest that intracellular lipid content is a key intrinsic determinant for hepatocyte heterogeneity of metabolic, inflammatory, and survival states.
肝脏是一个重要的代谢器官。除了代谢葡萄糖和脂质外，肝细胞还分泌各种细胞因子，调节肝细胞代谢和肝脏炎症。肝细胞损伤和死亡以及肝脏炎症是肝脏疾病（包括非酒精性脂肪性肝炎（NASH））的主要原因。解剖位置对肝细胞代谢有深远的影响，肝区描述了沿门静脉轴的肝细胞代谢异质性。然而，尚不清楚肝细胞异质性是否受内在因素的影响，以及膳食脂肪（NASH 的一个危险因素）是否对不同的肝细胞亚群有独特的不良影响。在这里，我们表明小鼠肝脏中存在富含脂质和低脂质的肝细胞亚群。富含脂质的亚群在接受内毒素和饱和脂肪酸处理后更容易受到损伤和凋亡，并产生更多的促炎细胞因子。膳食脂肪的消耗进一步增加了脂肪酸的摄取、细胞内脂质水平、肝细胞损伤和死亡，以及富含脂质亚群中促炎细胞因子的表达。相比之下，膳食脂肪仅略微增加了低脂质亚群的脂质水平、细胞死亡和促炎细胞因子的表达。低脂质亚群产生更多的葡萄糖。脂肪消耗进一步激活了低脂质亚群，但不是富含脂质亚群的糖异生程序。这些数据表明，细胞内脂质含量是决定肝细胞代谢、炎症和生存状态异质性的关键内在决定因素。
